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PMID: 20424607 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

A dicer-independent miRNA biogenesis pathway that requires Ago catalysis.

Nature ·Vol. 465 ·No. 7298 ·2010-06-03 ·Pages 584-9

Cheloufi S, Dos Santos CO, Chong MM, Hannon GJ

Abstract

The nucleolytic activity of animal Argonaute proteins is deeply conserved, despite its having no obvious role in microRNA-directed gene regulation. In mice, Ago2 (also known as Eif2c2) is uniquely required for viability, and only this family member retains catalytic competence. To investigate the evolutionary pressure to conserve Argonaute enzymatic activity, we engineered a mouse with catalytically inactive Ago2 alleles. Homozygous mutants died shortly after birth with an obvious anaemia. Examination of microRNAs and their potential targets revealed a loss of miR-451, a small RNA important for erythropoiesis. Though this microRNA is processed by Drosha (also known as Rnasen), its maturation does not require Dicer. Instead, the pre-miRNA becomes loaded into Ago and is cleaved by the Ago catalytic centre to generate an intermediate 3' end, which is then further trimmed. Our findings link the conservation of Argonaute catalysis to a conserved mechanism of microRNA biogenesis that is important for vertebrate development.

MeSH Terms
Alleles Anemia/genetics,metabolism Animals Argonaute Proteins Base Sequence Biocatalysis Embryo, Mammalian/embryology,metabolism Eukaryotic Initiation Factor-2/genetics,metabolism Homozygote MicroRNAs/biosynthesis Molecular Sequence Data Ribonuclease III/metabolism
Chemicals
Ago2 protein, mouse Argonaute Proteins Eukaryotic Initiation Factor-2 MicroRNAs Mirn451 microRNA, mouse Drosha protein, mouse Ribonuclease III
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Cheloufi Sihem
Cold Spring Harbor Laboratory, Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor, New York 11724, USA.
Dos Santos Camila O
Chong Mark M W
Hannon Gregory J
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature09092
Published
2010-06-03
Pages
584-9
Language
English
Region
England
NLM ID
0410462
PMCID
PMC2995450
Subset
IM
Grants
NCI NIH HHS · P01 CA013106 · United States
NCI NIH HHS · P01 CA013106-38 · United States
Howard Hughes Medical Institute · United States
Databases
GEO
GSE21370
Corrections
CommentIn
PMID: 20565849
CommentIn
PMID: 20571582
External Links
PubMed source DOI: 10.1038/nature09092 PMC Full Text View journal details
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